This invention relates to methods for treating benign gynecological disorders, reducing the risk of cancers of the breast and ovary, decreasing density on mammograms and decreasing breast parenchyma, as well as to formulations for use in such methods. More particularly, the present invention is directed to methods and preparations effective in treating benign gynecological disorders, including premenstrual syndrome, for extended periods of time. Pursuant to the method of the invention, ovarian hormone production is suppressed and only estrogens (and, optionally, androgens) are replaced in order to treat benign gynecological disorders; ovarian progesterone is not replaced. The formulations are for use in women in whom the risk of endometrial stimulation is minimized or absent. Such women include those who have had a prior hysterectomy, those who are using a progesterone releasing intrauterine device, and those who receive other progestogens from their physicians.
Gonadotropin releasing hormone (GnRH), also known as luteinizing hormone releasing hormone (LHRH), produced by the hypothalamus controls the secretion of follicle stimulating hormone (FSH) and luteinizing hormone (LH) by the pituitary and thence gonadal steroid hormone production. Potent synthetic agonists of GnRH administered to premenopausal women have been shown to produce a transient rise in FSH/LH release followed by a sustained suppression.
Inhibition of ovulation by GnRH agonists has been found, as expected, to be dose-related. When administered in a dose just high enough to ensure anovulation, the ovaries may continue to produce estrogen. This is an unstable situation, with different women having widely varying serum estrogen levels. There has also been concern that endometrial hyperplasia would occur in some women, while in others there would be periods of hypoestrogenemia with unacceptable vasomotor symptoms and probably loss of bone mineral content. "High-dose" GnRH agonists have been observed to uniformly reduce serum estradiol and serum progesterone to oophorectomized levels. The development of "high dose" depot formulations of GnRH agonists permits sustained inhibition of ovulation and suppression of ovarian steroid production, as well as improved ease of drug administration. The treatment is reversible; in a study of 50 patients, recovery of menstrual function occurred on average at 87 days (range 44-126 days following 6-8 months treatment with the GnRH agonist tryptorelin [Zorn, J. -R. et al., Fertil.Steril. 53:401-06 (1990)]. Other depot formulations of GnRH agonists produce similar sex-steroid suppresion including decapeptyl [George, M. et al., Int.J.Fertil. 34:19-24 (1989)], goserelin [Kaufman, M. et al., J.Clin.Oncol. 7:1113-19 (1989)] and buserline [Donnez, J. et at., Fertil.Steril. 51:947-50 (1989)].
In spite of their clear effectiveness, side effects attendant to the use of "high-dose" GnRH agonists have prevented their general adoption. Common side effects reported to occur with depot GnRH agonists in premenopausal patients include: hot flashes, vaginal dryness, irregular vaginal bleeding and fatigue. Additional side effects that have been reported in some patients receiving GnRH agonists include: sweating, headache, depression, lability in mood, nausea and/or vomiting, nervousness, insomnia, pollakisuria, weight gain, sleepiness, dizziness, decreased libido and mild breast tenderness or swelling.
A recent review article reflects current thinking about GnRH and its analogues [Conn, P. M. and Crowley, Jr., W. F., "Gonadotropin-Releasing Hormone and Its Analogues, "N.Engl.J.Med. 324:93-103 (1991)]. The The authors note at pages 96-97 that "whether to supplement GnRH-agonist analogues with sex steroids is a complex decision"; they propose estrogen replacement followed by the administration of a progestational agent "at physiologic doses and in a physiologic (i.e., sequential) pattern."
U.S. Pat.No. 4,762,717 to Crowley, Jr., the entire disclosure of which is hereby incorporated by reference, is based on the above-noted assumption that administration of a progestational agent should be effected in a sequential pattern so as to mimic the phases of the menstrual cycle. The patent describes contraceptive methods for female animals using luteinizing hormone releasing hormone (LHRH) compositions in combination with sex steroids. The patent calls for administering LHRH (or analogs, agonists or antagonists thereof) in a first delivery system combined with continuous administration of an effective amount of estrogenic steroids during the "follicular phase" of the menstrual cycle beginning at the onset of "normal menses". A second delivery system is administered during the "luteal phase" of the menstrual cycle until the onset of "normal menses". The second delivery system comprises the LHRH/estrogenic steroid combination and additionally provides an effective dosage of a progestational steroid.
This administration sequence is designed to mimic the physiological secretion of steroids in the menstrual cycle. As a consequence, each delivery system is effective for a period of only about two weeks (corresponding to the typical length of each of the follicular and luteal phases, according to the designation of Crowley).
The approach of Crowley is clearly unacceptable when considered in light of current knowledge about the long-term effects of administering the components thereof for the periods of time specified. The proposed level of estrogen administration (i.e., to achieve an estradiol concentration of about 50 to about 140 pg/ml for a human female) in the two delivery system approach of Crowley is unnecessarily high and the proposed amount of progestogen to be administered unnecessarily high. Epidemiologic case-control studies of postmenopausal breast cancer risk and estrogen replacement therapy (ERT) using population controls suggest that increased exposure to exogenous estrogen leads to an increased risk of breast cancer in a dose-dependent fashion. Moreover, administration of progestational steroid for about two weeks of every approximately 28-day treatment cycle was associated with unacceptable risks to the patient in a recent epidemiological study of breast cancer [Bergkvist, L. et al., N.Engl.J.Med. 321:293-97 (1989)]: the study suggests that the addition of progestogen during the latter half of the 28-day ERT cycle may double the risk associated with use of estrogen alone.
Pike, M. C. et al., Br. J. Cancer 60:142-48 (1989), the entire disclosure of which is also hereby incorporated by reference, have proposed a contraceptive regimen in which "high-dose" LHRH agonist treatment is coupled with estrogen replacement therapy (ERT), specifically 0.625 mg of conjugated equine estrogens for 21 days in each 28-day treatment cycle. The administration of a progestational steroid is proposed to be limited to a 10-16 day interval every three or four cycles. It is now clear that the 7-day period in each treatment cycle when ERT is not provided would be associated in many patients with symptoms of estrogen withdrawal, such as hot flushes. Moreover, a negative calcium balance could develop during the period of hypoestrogenemia with the possibility of resultant osteoporosis. Finally, blood cholesterol levels would likely be adversely affected during that time. Therefore, it is unlikely that the specific regimen proposed by Pike et al. would be found acceptable.
Administration of various compositions comprising sex hormones has also been contemplated in connection with the treatment of various benign gynecological disorders, such as endometriosis, fibroids and polycystic ovarian syndrome. One particularly prevalent disorder for which hormonal therapy has been contemplated is late luteal phase dysphoric disorder (commonly referred to as premenstrual syndrome). The essential feature of late luteal phase dysphoric disorder is a pattern of clinically significant emotional and behavioral symptoms that occur during the last week of the luteal phase and remit within a few days after the onset of the follicular phase. In most females, these symptoms occur in the week before and remit within a few days after the onset of menses. Non-menstruating females who have had a hysterectomy but retain ovarian function may also report similar symptoms. Among the most commonly experienced symptoms are the following: marked affective lability (e.g., sudden episodes of sadness or irritability); persistent feelings of irritability, anger or tension; feelings of depression and self-deprecating thoughts; decreased interest in usual activities; fatigue and loss of energy; a subjective sense of difficulty in concentrating; changes in appetite; cravings for specific foods; sleep disturbance; breast tenderness or swelling; headaches; joint or muscle pain; a sensation of bloating; and weight gain. The symptoms are often so severe as to seriously interfere with work or with usual social activities or relationships with others.
It has been reported that administration of a GnRH agonist may ameliorate some of the symptoms of premenstrual syndrome [Mortola, J. F. et al., J. Clin. Endocrin. & Metab. 72:252A-252F (1991)]. In addition to administration of GnRH agonist alone, the study included in a 28-day regimen combinations of GnRH agonist with conjugated equine estrogen (CEE) on days 1-25, with medroxyprogesterone acetate (MPA) on days 16-25, and with both CEE on days 1-25 and MPA on days 16-25. The authors concluded that the use of 0.625 mg CEE on days 1-25 and 10 mg MPA on days 16-25 would provide a safe and effective method of obtaining the beneficial effects of GnRH agonist on premenstrual syndrome. Unfortunately, this type of regimen (calling for addition of progestogen during the latter half of each 28-day ERT cycle) for treatment of premenstrual syndrome would be subject to the same objections previously noted for comparable contraceptive regimens, i.e., a possible doubling of the breast cancer risk associated with use of estrogen alone (Bergkvist et al., supra).
Androgens have been administered in these settings to improve sexual functioning, but there are significant negative effects. The administration of even a low dose (e.g., 1.25 to 2.5 mg) of an oral androgen, such as methyltestosterone, with oral estrogens is associated with detrimental changes in blood cholesterol patterns [Notelovitz, M. et al., "Influence of extended treatment with oral estrogens/androgen combination on lipids and lipoproteins in surgically menopausal women, "North American Menopause Society, 1991, Meeting Abstract S-B5 (Montreal, Canada 1991); Youngs, D. D. & Sherwin, B. B., "Effects of an oral estrogen-androgen preparation on lipoprotein lipids in postmenopausal women: a pilot study," North American Menopause Society, 1991, Meeting Abstract P-130 (Montreal, Canada 1991). The addition of testosterone implants to estrogen appears to have only a small impact on cholesterol patterns. While it may negate the positive beneficial effects of the estrogen on cholesterol, a detrimental effect is not clearly seen [Farish, E. et al., "The effects of hormone implants on serum lipoproteins and steroid hormones in bilaterally oophorectomized women," Acta Endocrinologica 106: 116-20 (1984)].
The use of pellets of testosterone unfortunately results in large variations in serum levels of testosterone over time. High levels are observed shortly after administration [Burger, H. G. et al., "The management of persistent menopausal symptoms with estradiol-testosterone implants: clinical, lipid and hormonal results," Maturitas 6: 351-8 (1984)]. Elevated serum testosterone levels with associated virilization or masculinization can occur with repeated administration, if caution is not used [Urman, B. et al., "Elevated serum testosterone, hirsutism, and virilism associated with combined androgen-estrogen hormone replacement therapy, "Obstet. Gynecol. 77: 595-8 (1991)]. Further, the serum testosterone levels achieved with such approaches may be substantially above usual levels is normal premenopausal women [Sherwin, B. B. et al., "Postmenopausal estrogen and androgen replacement and lipoprotein lipid concentrations," Am. J. Obstet. Gynecol. 156: 414-9 (1987)].
It is an object of the present invention to provide a regimen which would obviate a number of problems attendant to existing treatments of various benign gynecological disorders in women in whom the risk of endrometrial stimulation is minimized or absent, while at the same time reducing the risk of adverse consequences associated with the heretofore known methods.